The effects of retinoic acids on gene expression is mediated by ligand-inducible transcription factors known as retinoid nuclear receptors. The retinoid X receptor (RXR), which is activated by the vitamin A derivative 9-cis-retinoic acid, is unique in that it can function as a homodimer, but can also associate with other nuclear receptors, as for example, the vitamin D-, the retinoic acid-, and thyroid homone-receptors, and thus plays a central role in regulating several signaling pathways at the level of the genome. We are interested in the molecular mechanisms by which the activities of retinoid receptors are regulated. We previously demonstrated that RXR forms tetramers with a high affinity and that the self-association of the receptor is tightly regulated by its cognate ligand. Over the past year we investigated the role of tetramer formation by RXR in regulating the receptor's transcriptional activity, and identified the location of the protein region that mediates tetramer formation. Mutational analyses indicated that this region critically containes two phenylaline residues located in helix 11 at the carboxyl terminus of the protein. Computer modeling of possible protein-protein interactions between two RXR dimers further supported the proposed location of the tetramerization interface. These findings, combined with the additional observations that ligand-induced dissociation of RXR tetramers is critical for the transcriptional activity of the receptor, led us to propose that the tetramerization region is impotant for the receptor's transcriptional activity. Ongoing studies are focusing on the implications of tetramer-formation by RXR for its interactions with other nuclear receptors. In addition, studies aimed at deciphering the role of the receptor's tetramerization interface in transcriptional regulation by RXR are in progress.